Genetic Susceptibility to Chronic Kidney Disease - Some More Pieces for the Heritability Puzzle.

Amy Jayne McKnight,Marisa Cañadas-Garre,Kerry Anderson,Laura Jane Smyth,Ruaidhri Cappa,Ryan Skelly,Alexander Peter Maxwell

doi:10.3389/fgene.2019.00453

Amy Jayne McKnight, Marisa Cañadas-Garre + Show 5 more

Open Access

https://doi.org/10.3389/fgene.2019.00453

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Abstract

Chronic kidney disease (CKD) is a major global health problem with an increasing prevalence partly driven by aging population structure. Both genomic and environmental factors contribute to this complex heterogeneous disease. CKD heritability is estimated to be high (30–75%). Genome-wide association studies (GWAS) and GWAS meta-analyses have identified several genetic loci associated with CKD, including variants in UMOD, SHROOM3, solute carriers, and E3 ubiquitin ligases. However, these genetic markers do not account for all the susceptibility to CKD, and the causal pathways remain incompletely understood; other factors must be contributing to the missing heritability. Less investigated biological factors such as telomere length; mitochondrial proteins, encoded by nuclear genes or specific mitochondrial DNA (mtDNA) encoded genes; structural variants, such as copy number variants (CNVs), insertions, deletions, inversions and translocations are poorly covered and may explain some of the missing heritability. The sex chromosomes, often excluded from GWAS studies, may also help explain gender imbalances in CKD. In this review, we outline recent findings on molecular biomarkers for CKD (telomeres, CNVs, mtDNA variants, sex chromosomes) that typically have received less attention than gene polymorphisms. Shorter telomere length has been associated with renal dysfunction and CKD progression, however, most publications report small numbers of subjects with conflicting findings. CNVs have been linked to congenital anomalies of the kidney and urinary tract, posterior urethral valves, nephronophthisis and immunoglobulin A nephropathy. Information on mtDNA biomarkers for CKD comes primarily from case reports, therefore the data are scarce and diverse. The most consistent finding is the A3243G mutation in the MT-TL1 gene, mainly associated with focal segmental glomerulosclerosis. Only one GWAS has found associations between X-chromosome and renal function (rs12845465 and rs5987107). No loci in the Y-chromosome have reached genome-wide significance. In conclusion, despite the efforts to find the genetic basis of CKD, it remains challenging to explain all of the heritability with currently available methods and datasets. Although additional biomarkers have been investigated in less common suspects such as telomeres, CNVs, mtDNA and sex chromosomes, hidden heritability in CKD remains elusive, and more comprehensive approaches, particularly through the integration of multiple –“omics” data, are needed.

Highlights

Chronic kidney disease is a major global health problem with an increasing prevalence (Levey et al, 2007; Bash et al, 2009; Centers for Disease Control and Prevention, 2015)
The molecular mechanisms that trigger the formation of copy number variants (CNVs) are not fully understood, but recurrent CNVs with common breakpoints reportedly arise through unequal meiotic or non-allelic homologous recombination (Arlt et al, 2012)
Recent evidence has suggested that de novo and nonrecurrent CNVs may develop following either replicative errors, chromosome shattering or chromothripsis (Kloosterman et al, 2011; Arlt et al, 2012; Nazaryan-Petersen et al, 2018)

Summary

Introduction

Chronic kidney disease is a major global health problem with an increasing prevalence (Levey et al, 2007; Bash et al, 2009; Centers for Disease Control and Prevention, 2015). By 2040, it is estimated that CKD will have become the fifth leading cause of death (Foreman et al, 2018). This increasing CKD burden is driven in part by aging population structure (CKD is ∼8x more common in adults > 70 years old compared to persons < 40 years of age) (Bash et al, 2009; Centers for Disease Control and Prevention, 2015). Diabetes and hypertension are common risk factors for kidney damage (Kazancioglu, 2013) and are major contributors to the increased CKD prevalence (Bash et al, 2009). Women have a lower risk of CKD progression and men are more likely to develop ESRD (Ricardo et al, 2018)

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